Neural Mechanisms of Anorexia

项目摘要/摘要 这些实验的长期目标是定义负责的神经网络的组织 厌食症大鼠。特别是studieswillfocusoninteractionsbetweenthetelencephalon，和下丘脑 后脑，因为端脑可能在临床相关的厌食症中起着关键作用。生成 在厌食症的实验中，该项目将使用饮用高渗盐水后的慢性脱水。 这种有据可查的模式的优点是，它的开发和强度可以简单可靠 控制住了。此外，当动物喝水时，厌食症很快就会逆转。主要假设 下丘脑外侧区和下丘脑室旁核含有神经元 这构成了一个摄食行为控制器，并且是不同的摄食刺激汇聚到控制的地方 驱动馈电的核心电路。目标是确定汇聚点的位置，以及 以探索在厌食症期间这些因素是如何受到影响的。具体目标将涉及三个假设。 它们是：1)编码伏隔核壳(ACBsh)-蝇酚和2-脱氧-D-葡萄糖的信息- 驱动摄食汇聚到LHA和PVH中的相同神经元；2)ACBsh-Muscimol摄食需要 后脑或NPY-Y1受体在下丘脑内侧基底区表达神经元的输入 (MBH)全表达；3)来自后脑或NPY-Y1受体表达神经元的投射 回水进料需要MBH至PVH和LHA。实验将使用两种方法：第一， 对照中ACBsh-Muscimol和2-脱氧-D-葡萄糖驱动的饲喂结构的细粒度分析 和厌食动物；第二，一种新的免疫细胞化学符合检测(基于区分 Fos和磷酸化ERK/2的积累和降解率)，揭示了 由两个会聚的摄食刺激激活。电路将使用基于皂苷的免疫毒素进行操作 破坏后脑上行儿茶酚胺能神经元或NPY-Y1受体的损伤 MBH内神经元的表达。重要的是，影响这两种技术的喂养类型 显然是不合群的。总体而言，本项目中的实验旨在做出重大贡献 为了阐明导致动物厌食症的神经回路的组织和功能 一种最终将有助于阐明临床上重要厌食症的神经基础的方法。项目叙事 进食障碍，尤其是神经性厌食症，是严重的临床问题，结果很差； 事实上，神经性厌食症是所有精神疾病中最致命的之一。饮食失调的治疗 这是出了名的困难，药物干预令人沮丧地无效。建议进行的研究 目的描述产生一种实验上可治疗的厌食症的神经回路。 在动物身上，以期开发可应用于临床相关的神经网络模型 厌食症。

PROJECT SUMMARY/ABSTRACT The long-term goal of these experiments is to define the organization of the neural networks responsible for anorexiainrats.Inparticular,studieswillfocusoninteractionsbetweenthetelencephalon,andthehypothalamus and hindbrain, since the telencephalon likely plays a critical role in clinically-relevant anorexias. To generate anorexia experimentally, the project will use the chronic dehydration that follows drinking hypertonic saline. This well-documented model has the advantage that its development and intensity can be simply and reliably controlled. Furthermore, the anorexia is quickly reversed when the animal drinks water. The main hypothesis is that the lateral hypothalamic area and the paraventricular nucleus of the hypothalamus contain neurons that constitute a ¿feeding behavior controller¿, and are sites where distinct feeding stimuli converge to control the core circuits that drive feeding. The goal is to determine the locations of the points of convergence, and to explore how these are affected during anorexia. Three hypotheses will be addressed by the specific aims. They are: 1) Information encoding nucleus accumbens shell (ACBsh)-muscimol and 2-deoxy-D-glucose- driven feeding converges onto the same neurons in the LHA and PVH; 2) ACBsh-muscimol feeding requires input from either the hindbrain or NPY-Y1 receptor expressing neurons in the mediobasal hypothalamus (MBH) for full expression; 3) projections from either the hindbrain or NPY-Y1 receptor expressing neurons in the MBH to the PVH and LHA are required for water-back feeding. Experiments will use two approaches: first, a fine-grained analysis of the structure of ACBsh-muscimol and 2-deoxy-D-glucose-driven feeding in control and anorexic animals; second, a novel immunocytochemical coincidence detection (based on the differential accumulation and degradation rates of Fos and phosphorylated-ERK/2) that reveals neurons that are activated by two convergent feeding stimuli. Circuits will be manipulated using saporin-based immunotoxic lesions that destroy either the ascending catecholaminergic neurons from the hindbrain, or NPY-Y1 receptor expressing neurons in the MBH. Importantly, the types of feeding that are impacted these two techniques are clearly dissociable. Collectively, the experiments in this project are designed to make major contributions towards elucidating the organization and function of the neural circuits responsible for anorexia in animals in a way that will ultimately help to clarify the neural substrates of clinically important anorexias. PROJECT NARRATIVE Eating disorders, and anorexia nervosa in particular, are significant clinical problems that have poor outcomes; indeed, anorexia nervosa is one of the deadliest of all psychiatric disorders. Treatment of eating disorders is notoriously difficult, with pharmacological intervention being frustratingly ineffective. The proposed studies aim to delineate the neural circuitry responsible for generating an experimentally-tractable type of anorexia in animals, with a view to developing neural network models that can be applied to clinically-relevant anorexias.